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PubMed1990

Expression of HRF20, a regulatory molecule of complement activation, on peripheral blood mononuclear cells.

HRF20 is a homologous restriction factor of 20,000 MW that prevents cells from membrane attack by homologous complement. HRF20 has been identified by a monoclonal antibody (mAb), 1F5, and is one of the phosphatidylinositol(PI)-anchored cell-surface glycoproteins. We analysed the distribution of HRF20 expressed on subsets of peripheral blood lymphocytes using 1F5. HRF20 is expressed in relatively large amounts on T cells. In contrast, adherent cells possess smaller amounts of HRF20 while having large quantities of decay-accelerating factor (DAF). Although DAF was shown to be deficient or present at rather low levels on NK cells, HRF20 was detected in 95% of large granular lymphocytes (LGL), as described by FACS analysis. We also determined the effect of 1F5 on both mononuclear leucocytes and T cells in terms of their growth response. The results show that 1F5 induces T-cell proliferation when cells are stimulated with interleukin-2 (IL-2). In addition, induction of proliferation is facilitated by cross-linking 1F5 with a second antibody. These results suggest that HRF20 expressed on T cells not only protects them from cytotoxic attack by homologous complement, but also may initiate intracellular signals leading to cell activation when they happen to be cross-linked.

Antibodies, Monoclonal↗
PubMed1991

Quantitative analysis of adenine nucleotides during the prelytic phase of cell death mediated by C5b-9.

The nucleated cell death mediated by C5b-9 depends on the extent of C fixation and parameters that affect the ability of the cell to eliminate C5b-9. When C5b-9 formation exceeds elimination, cell death can be initiated. High Ca2+ in the medium accelerates Ehrlich ascites cell death induced by a large number of C5b-9, whereas osmotic prevention of cell swelling has little effect in protecting Ehrlich cells from killing by C5b-9. In the present study, we investigated the interrelationship between intracellular Ca2+, intra- and extracellular adenine nucleotides, and mitochondrial membrane potential, to understand the mechanism of acute cell death induced by C5b-9. When Ehrlich cells carrying C5b-8 were exposed to C9, rapid and profound ATP depletion in the cell was observed before cell death. Leakage of the adenine nucleotides ATP, ADP, and AMP also began during the prelytic phase. Studies using digital imaging fluorescence microscopy showed that loss of mitochondrial membrane potential was noted immediately after C9 addition but before nuclear staining with propidium iodide. These findings suggest that an increase in intracellular Ca2+ through C5b-9 channels and loss of mitochondrial membrane potential may initiate rapid cell death. The prelytic leakage of ATP precursors may also contribute to cell death by decreasing nucleotide pools, because recovery of ATP production was observed after a similar degree of ATP loss in cells exposed to sublethal doses of KCN, in which ADP and AMP leakage was not present.

Adenine Nucleotides↗
PubMed1990

Recurrent meningitis in a patient with congenital deficiency of the C9 component of complement. First case of C9 deficiency in Europe.

We describe the first cases, to our knowledge, of C9 deficiency in Europe that were detected in a Swiss family, of which two members--one with a complete deficiency and the other with approximately half-normal C9 levels--experienced bacterial meningitis. The index patient, a 56-year-old white man with a history of purulent meningitis at the age of 23 years, presented with an acute meningococcal meningitis. No impairment of cellular immunity or immunoglobulin deficiency could be found. Complement assays showed a complete deficiency of the C9 component, while the other individual component levels were normal and the hemolytic activity (measured using the CH50 assay) was only slightly reduced. A family study revealed complete C9 deficiency in the patient's healthy brother and half-normal C9 concentrations in his sister, his son (who also had experienced an episode of bacterial meningitis), and his niece, consistent with an inherited C9 deficiency. This first case of recurrent meningitis in a white patient with complete C9 deficiency suggests that this complement defect may also be a risk factor for bacterial, especially neisserial, infections.

Complement C9↗
PubMed1989

Interaction of fluid phase C1/C1q and macrophage membrane-associated C1q with gram-negative bacteria.

Many gram-negative bacteria are killed after treatment with normal non-immune sera and directly bind and activate C1 in the absence of antibodies. For the immediate killing of such serum-sensitive bacteria, like R-forms of Salmonella strains, all serum complement components are essential. When purified serum C1 to C9 are used, further activation of the cascade requires an additional serum factor. This glycoprotein differs from antibody and mediates the attachment of C4b to the bacterial cell surface. The antibody-independent interaction with C1 occurs via C1q, which binds to LPS. In addition outer membrane proteins bind C1q and C1. The association of these porins with LPS may potentiate the antibody-independent C1q and C1 binding to serum-sensitive bacteria. Porins can contribute to complement activation mainly through the classical pathway. LPS and porins from bacterial cell walls are also involved in the binding of gram-negative bacteria to macrophages. This antibody-independent attachment and ingestion of gram-negative bacteria is mediated by endogenous macrophage-membrane associated C1q.

Animals↗
PubMed1989

Complement-dependent cytotoxicity of antibodies reactive with HIV-induced cell surface antigens in HIV-carrying haemophiliacs.

Sera obtained from HIV-infected as well as uninfected haemophiliacs and from healthy subjects were investigated for the presence of lymphocytotoxic antibodies. Using the 51Cr-release test, HIV-infected haemophiliacs were found to produce serum antibodies exerting complement-dependent cytotoxic effect on HIV-infected T4 cells. The antibodies were reactive mainly when HIV-infected target cells were stimulated with concanavalin-A. Results of complement-dependent antibody cytotoxicity and indirect membrane immunofluorescence tests suggest that envelope antigen(s) of HIV may be the target(s) for cytotoxic antibodies.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Relative contributions of chemo-attractant and terminal components of complement to anti-glomerular basement membrane (GBM) glomerulonephritis.

The relative contributions of chemo-attractant and terminal components of complement to heterologous phase glomerular injury was studied in anti-GBM glomerulonephritis in rabbits. Normal rabbits (complement intact) were given anti-GBM antibody at a dose which resulted in 140 micrograms specific kidney-fixed antibody per gram of renal cortex, and developed significant proteinuria (1910 +/- 327 mg/24 h; control 18.2 +/- 6.1 mg/24 h; P less than 0.01). Leucocyte depletion significantly reduced but did not abolish proteinuria (574 +/- 186 mg/24 h, P less than 0.05). Complement depletion of neutrophil-depleted rabbits resulted in a further significant reduction in proteinuria 50.1 +/- 12.2 mg/24 h, P less than 0.05; versus neutrophil-depleted, complement-intact rabbits), indicating that both neutrophil accumulation and complement activation independent of neutrophils contribute to injury in this model. Rabbits congenitally deficient in the sixth component of complement (C6D) developed similar levels of proteinuria (2099 +/- 796 mg/24 h) to normal rabbits given an identical dose of antibody. However, after leucocyte depletion, C6D rabbits developed significantly less proteinuria (135 +/- 56 mg/24 h) than did leucocyte-depleted, complement-intact rabbits (P less than 0.05). These studies show that terminal complement components are not necessary for the full expression of acute anti-GBM antibody-initiated injury in leucocyte-intact rabbits. However, in the absence of leucocytes, C6 and the terminal complement components are apparently responsible for the majority of the complement-dependent glomerular injury.

Animals↗
PubMed1989

Interstitial nephritis induced by protein-overload proteinuria.

Experimental nephrotic syndrome induced by several immunologic and biochemical methods is associated with the development of tubulointerstitial nephritis (TIN). To investigate the hypothesis that severe sustained proteinuria plays a role in the pathogenesis of TIN, the renal interstitium in a model of protein-overload proteinuria was studied. After uninephrectomy, rats received daily injections of 1.0 g of bovine serum albumin (BSA) or saline (controls) until killing at 1, 2, 4, or 7 weeks. Sections of frozen renal cortex were stained with a panel of monoclonal antibodies reactive with subsets of rat lymphohemopoietic cells, and positive tubulointerstitial cells (TIC) were quantitated by epifluorescence microscopy. BSA rats developed proteinuria, with mean rat urinary albumin excretion rates at 1, 2, 3, and 6 weeks of 35.6 +/- 21.8, 97.2 +/- 46.1, 63.6 +/- 40.8, and 58.6 +/- 24.4 mg/24 hours, respectively (controls, 0.17 +/- 0.16 mg/24 hours). BSA was detectable in the plasma of experimental animals at all periods, with mean values of 26.8 +/- 3.8, 27.8 +/- 2.7, 20.3 +/- 6.2, and 7.0 +/- 1.1 mg/ml (controls, 0.03 +/- 0.04 mg/ml) at 1, 2, 4, and 7 weeks, respectively, whereas plasma anti-BSA antibodies were never detected. A significant mononuclear cell infiltrate was present in the interstitium of experimental animals at all periods. At 1 week, an influx of macrophages was evident that was identified by surface markers OX42 (75+/1000 TIC) (P less than 0.01) and Ia (58+/1000 TIC) (P less than 0.01). Macrophages dominated the infiltrate at all periods. By 2 weeks, a significant population of lymphocytes was also present that was identified by the surface marker OX19 (54+/1000 TIC) (P less than 0.01). This early lymphocytic infiltrate was a mixed lesion of T helper and T cytotoxic cells. However, at 4 and 7 weeks, most lymphocytes expressed the OX8 cytotoxic T cell marker. The proximal tubules of proteinuric rats expressed vimentin intermediate filaments, a marker of tubular epithelial cell regeneration after injury. In BSA rats, C3 and neoantigens of the membrane attack complex of complement without IgG were present along the luminal border of many tubular epithelial cells. The interstitial infiltrate was confirmed by light microscopy. By 4 weeks, focal areas of chronic interstitial disease were evident consisting of tubular atrophy and interstitial fibrosis. In a second study, one group of BSA-treated rats was depleted of circulating T lymphocytes by daily parenteral injections of monoclonal antibody OX19.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

The pathogenetic significance of C5b-9 in IgA nephropathy.

Renal biopsies from 20 patients with IgAN were retrospectively studied using monoclonal antibodies against T cells, monocytes/macrophages (MM), HLA-DR-related antigen and the C5b-9 neoantigen. Glomerular C5b-9 deposits were mainly found in the mesangial areas and showed an association with IgA (P < 0.005) and C3 deposits (P < 0.001). Interstitial T cells and MM were highly correlated with the interstitial DR + ve cells (P < 0.001 and P < 0.0005 respectively). Tubular C5b-9 deposition was observed on the tubular basement membranes and related to the numbers of interstitial T cells (P < 0.005), MM (P < 0.005) and DR + ve cells (P < 0.01) as well as to the tubular DR expression (P < 0.025). The severity of tubular atrophy and interstitial fibrosis showed a positive correlation with the interstitial T cells, MM and DR + ve cells, as well as with the intensity of tubular C5b-9 deposition (P < 0.05 and P < 0.05 respectively). Plasma creatinine on presentation was correlated with the numbers of interstitial T cells (P < 0.05), MM (P < 0.01), interstitial DR + ve cells (P < 0.005), and tubular C5b-9 deposits (P < 0.005). No correlation between glomerular T cells, MM, and C5b-9 deposits with plasma creatinine was seen. During follow-up, renal function deteriorated in those patients with the more extensive tubular C5b-9 deposits. In conclusion, glomerular C5b-9 deposition seems to be secondary to the IgA and C3 deposition. In contrast, tubular C5b-9 is related to the numbers of interstitial T cells and MM. Activated interstitial mononuclear cells may lead to the tubular deposition of C5b-9, which eventually might contribute to the development of tubulointerstitial lesions (TIL) and renal function impairment.

Adult↗
PubMed1994

Complement-inhibiting activities of human CD59 and analogues from rat, sheep, and pig are not homologously restricted.

Human erythrocyte CD59 and analogues isolated from erythrocytes of rat, sheep, and pig were examined for their ability to protect erythrocytes from various species against lysis by C from homologous and heterologous sources. In all cases, incorporation of human CD59 or analogues from rat, sheep, and pig efficiently protected guinea pig erythrocytes against lysis by C homologous with the CD59. However, each of the CD59 analogues also conferred on guinea pig erythrocytes protection against C from most heterologous species. These results demonstrate that none of the CD59 analogues tested were species specific in their C-inhibiting activity. Erythrocytes from species other than guinea pig could not be protected by incorporation of any of the available CD59 analogues despite similar incorporation in all erythrocytes tested. We suggest that the presence of endogenous inhibitors on these other erythrocytes masks the activity of incorporated CD59. Evidence that is supportive of this hypothesis was provided by demonstrating that blocking the endogenous CD59 with mAbs rendered erythrocytes susceptible to inhibition by high dosages of incorporated CD59.

Animals↗
PubMed1995

[Vitronectin in children with renal disease--1. Immunofluorescence study of vitronectin and C5b-9 in childhood IgA nephropathy].

Renal biopsy specimens from 54 children (33 boys, 21 girls) with IgA nephropathy were investigated by immunofluorescence microscopy to determine the localization of vitronectin and C5b-9. vitronectin and C5b-9 deposits were found within the glomeruli of all cases and the intensity of vitronectin and C5b-9 deposits was as follows: vitronectin: (3+) 17 cases, (2+) 21 cases, (1+) 16 cases and C5b-9: (3+) 28 cases, (2+) 18 cases, (1+) 8 cases. In 19 cases and C5b-9 deposits were shown to be more predominant than vitronectin (Group C) and the same or less intense in 35 cases (Group V). In 33 cases, vitronectin deposits were demonstrated in the mesangial area only (M type), while in 21 cases deposits were presented both the mesangial area and the capillary wall (MC type). Linear staining of vitronectin was noted in Bowman's basement membrane and in the tubular basement membrane. Granular staining of vitronectin was observed in Bowman's basement membrane (29 cases) and tubular basement membrane (46 cases). M type C5b-9 deposits were demonstrated in 34 cases and MC type in 20 cases. C5b-9 deposits were observed in Bowman's basement membrane (19 cases) and in tubular basement membrane (37 cases). Intensely stained vitronectin was found in the sclerotic glomeruli and segmental sclerotic portion of the tissues. In serial biopsy, the intensity of both vitronectin and C5b-9 deposits became less intense. It was found that many patients of Group C had heavy proteinuria (P < 0.05) and that nephrotic patients were more frequent in Group C than in Group V (p < 0.05). In the light microscopic examination, most cases with intense C5b-9 deposits had mesangial proliferation (p < 0.10) and an increase in mesangial matrix (p < 0.10). Mesangial sclerosis index was correlated with the intensity of vitronectin deposits (p < 0.05). These findings suggest that vitronectin and the terminal complement system may play a critical role as a mediator of immunological tissue injury, especially mesangial sclerotic lesion in childhood IgA nephropathy.

Adolescent↗
PubMed1994

Clusterin gene expression in the rat thymus is not modulated by dexamethasone treatment.

Clusterin, a multifunctional glycoprotein, characterized as a potent inhibitor of the membrane attack complex of complement, is also known to be the product of a gene that is highly up-regulated in certain tissues undergoing programmed cell death. We have studied the expression of this gene in the rat thymus after the induction of thymocyte programmed cell death (PCD) by in vivo dexamethasone administration. Northern blot analysis of clusterin mRNA 2, 4, 6 and 8 hr after dexamethasone administration in a total of 21 rats revealed no modification in the level of clusterin gene expression. In situ hybridization demonstrated that clusterin gene expression is macroscopically confined to the medullary region of the thymus, and that this distribution is not modified by dexamethasone administration. These results strongly suggest that in the rat, clusterin gene expression is not associated with the programmed cell death of thymocytes following in vivo dexamethasone administration. In situ hybridization of the clusterin cRNA to thymus cryostat sections confirmed the results obtained by Northern blot analysis. Indeed, no consistent increase in the amount of clusterin mRNA was detectable at any of the time-points studied. The macroscopic distribution of clusterin mRNA in the rat thymus was identical to that previously observed in the human thymus, clusterin message being essentially detected within the medullary regions. No modification in the macroscopic distribution of clusterin gene expression was detected after dexamethasone administration. These results suggest that, like the human thymus, medullary epithelial cells are the site of clusterin gene expression in the rat thymus. Moreover they indicate that an increase in the extent of ongoing thymocyte PCD does not significantly modify the rate or site of clusterin gene expression within the thymus.

Animals↗